Various techniques for forming orally administrable edible agents such as drugs, quasi drugs, cosmetics and food into a shape of a sheet or a film have been proposed.
For example, Patent Documents 1 and 2 describe a method for producing food having a multilayer structure by feeding edible materials of different types and/or blend-ratio into hopper-chambers respectively which are partitioned off a hopper by partition plates, forming a plurality of primary rolled sheets of strip form by a primary common mill roll below the hopper-chambers, superposing the sheets one on another with a certain space therebetween in a direction perpendicular to a longitudinal direction of the sheets during conveyance, and rolling the superposed sheets by a secondary mill roll to bond them to each other. This method is, however, adapted to form a thick multilayer sheet having plasticity by rolling, and cannot produce orally administrable edible agents such as drugs, food, etc. formed by pressure bonding edible materials of several hundreds μm to several tens μm thick into a multilayer structure of several thousands μm to several tens μm thick.
The following is a patent document that relates to obtaining an edible multilayer structure of film form such as drugs, food, etc. of several thousands μm to several tens μm thick.
Patent Document 3 describes a preparation of sheet or tape form for administering buprenorphine to oral mucosa, a producing method including a first step of dissolving buprenorphine or a pharmacologically comparable substance in a suitable hydrophile solvent together with a water-soluble polymer capable of film formation, optionally in presence of further dissolved or suspended auxiliary agents; a second step of applying the solution or suspension to a tape or a process sheet or a foil with even thickness in a continuous process; a third step of removing most of the solvent to form a sheet-shaped or tape-shaped starting material; and a fourth step of separating the starting material by cutting or punching out into the dosage or multidosage units, and a producing method for combining the plurality of sheet-shaped or tape-shaped materials so as to form a multilayered material, but does not teach at all a specific method for producing a multilayer structure.
Patent Document 4 describes an orally administrable agent of film form having a multilayer structure including a drug-containing layer containing a water-soluble polymer as a main base ingredient, a non-adhesive layer (a difficultly water-soluble layer) that is difficultly water-soluble and placed on one surface of the drug-containing layer, and a powdery adhesive substance placed on the other surface of the drug-containing layer. As the powdery adhesive substance, carboxy vinyl polymer, polyacrylate such as sodium polyacrylate or a pharmaceutically accepted nontoxic salt thereof, acrylic acid copolymer or a pharmaceutically accepted nontoxic salt thereof, a hydrophilic cellulose derivative such as carboxymethyl cellulose and sodium salt thereof, pullulan, povidone, karaya gum, pectin, xanthan gum, tragacanth, alginic acid, gum arabic, acidic polysaccharide or a derivative thereof or a nontoxic salt thereof can be used.
A producing method disclosed in an embodiment of the Patent Document 4 includes repeatedly spreading or spraying an edible layer solution and drying the spread or sprayed edible layer solution on a petri dish made of polytetrafluoroethylene to obtain an orally administrable agent of film form having a desired multilayer structure. Such a producing method cannot be industrially used, though used in a laboratory. Further, if an edible layer solution containing a different drug, an edible layer solution maintaining an adhesive polymer in a powdery state, or powder itself is manually spread or sprayed on the formed edible layer so as to form the multilayer structure, it is difficult to spread or spray an accurate amount of orally administrable agent solution or powder to prevent control of an accurate amount of drug ingredient, and the obtained multilayer orally administrable agent of film form cannot satisfy quantitative accuracy required for pharmaceutical preparations.
Patent Document 5 filed by the applicant of this application proposes an orally administrable troche agent of film form including three layers of a covering layer (a), a drug layer I (b), and a drug layer II (c) laminated in order of a-b-c-b-a. This document discloses a method for producing the orally administrable troche agent of film form including repeatedly coating and drying each edible layer solution (a coating liquid) on a polyester delamination film to form a desired multilayer laminated structure.
In producing the orally administrable troche agent of film form having the multilayer laminated structure described in the Patent Document 5 filed by the applicant of this application, the applicant uses a coating apparatus 50 for continuously coating and drying the coating liquid on a continuously moving resin film as shown in FIG. 9. The coating apparatus 50 guides a resin film 52 set to a resin film unwinding shaft 51 into a drying oven 55 through a nip between a guide roll 53 and a doctor roll 54, and winds up the resin film 52 on a resin film winding shaft 56, thereby continuously moving the resin film 52. In the meantime, a coating liquid 58 contained in a dam portion 57 for supplying the coating liquid is coated on the resin film, and at this time, a clearance between the resin film 52 on the guide roll 53 and the doctor roll 54 is adjusted to a predetermined dimension to obtain a predetermined coating amount (see the partial enlarged view). A coating layer 58a on the resin film 52 thus formed passes through the drying oven 55 and is dried by hot air uniformly blown from a hot air blowing device 59, and a resin film 60 provided with an edible layer is wound up on the winding shaft 56 into a roll.
Then, the edible layer-formed resin film 60 wound up on the winding shaft 56 into the roll is mounted to the unwinding shaft 51 again, the coating liquid 58 of the same or different composition is supplied to the dam portion 57 for coating and drying again, and the resin film is wound up on the winding shaft 56, thereby producing a resin film including laminated two edible layers. Repeating such coating and drying steps allows the orally administrable troche agent of film form having a desired multilayer structure to be produced with higher productivity than the conventional methods described above.
However, it has been found that even with the coating method as shown in FIG. 9, accurate control of a coating amount of the coating liquid 58 is difficult in producing the orally administrable edible agent of film form having the multilayer structure by repeating the coating and drying steps, and quantitative accuracy required for pharmaceutical preparations cannot be satisfied, like the conventional methods described above.
Specifically, in a first coating step, the clearance between the doctor roll 54 and the resin film 52 can be set to the predetermined dimension to accurately control the coating amount at a predetermined value. However, a thickness of a dried edible layer formed in a drying step after the first coating step varies depending on minor variation of condition of the drying step and environmental conditions such as daily temperature and humidity. Therefore, in a second coating step, even if the clearance dimension between the doctor roll 54 and the resin film 52 is accurately set, a coating thickness of the second edible layer further varies depending on variation of the coating thickness of the first edible layer, since a coating thickness of the coating liquid 58 is determined by a clearance between an upper surface of the first dried edible layer and the doctor roll 54. It is significantly difficult to measure the variation of the thickness of the first edible layer 58a after the drying step.
Such an inaccurate coating amount of the coating liquid tends to increase as the number of coating and drying steps increases. Further, as the number of coating and drying steps increases, drying time increases. More specifically, drying time for the second edible layer is 1.5 times longer than that for the first layer, and drying time for a third layer is twice longer than that for the first layer.    Patent Document 1: WO98/56266    Patent Document 2: Japanese Patent Laid-Open No. 2002-191343    Patent Document 3: National Publication of International    Patent Application No. 2001-506640    Patent Document 4: Japanese Patent No. 2791317    Patent Document 5: Japanese Patent Laid-Open No. 2001-288074